Amphetamines and closely related stimulant drugs are among the most highly abused psychoactive drugs. In many cases these drugs are abused for prolonged periods of time leading to progressive social and occupational deterioration, punctuated by periods of hospitalization for toxic psychosis. Studies in animals have shown that a number of amphetamine like drugs have prominent effects on several neurotransmitter systems in the central nervous system, in particular dopamine and serotonin neuronal systems. The alterations in these monoaminergic systems occur in many animal species including mice, cats, guinea pigs and monkeys. The fact that amphetamines are neurotoxic to a number of species raises the possibility that such effects occur in humans. In contrast to the extensive literature documenting the neurotoxicity of amphetamines on monoaminergic systems of the brain very little research has been conducted on possible neurotoxic effects of cocaine. This grant proposes to study possible neurotoxic effects of methamphetamine and cocaine on dopamine and serotonin neurons in rat brain. Since there have been some reports of methamphetamine reducing norepinephrine concentrations in brain, uptake sites for this neurotransmitter will be examined also. Quantitative autoradiography will be used to study the distribution of binding sites for 3H-GBR 12935 and 3H- cyanoimipramine, ligands which bind to pre-synaptically located dopamine and serotonin uptake sites respectively. Norepinephrine uptake sites will be labelled using either 3H-desmethylimipramine or 3H-mazindol (measured as the difference in the binding in the absence and presence of desmethylimipramine). These studies will allow for an assessment of possible regional difference in sensitivity to the neurotoxic effects of these drugs of abuse.